Maintaining product stability during the various drug product process unit operations is paramount to our ability to supply safe and efficacious biotech products to patients. New technologies are helping us ensure that we meet these challenges successfully and are able to embrace the Quality by Design paradigm. This article presents best practices to meet three of the significant technical challenges experienced in drug product manufacturing, namely, maintaining product stability during frozen storage, performing visual inspection of drug product vials, and controlling protein particulates.

(Althea Technologies, Inc.)

Drug product manufacturing has its share of operational and technical challenges. The large number of stock-keeping-units (SKUs) that we typically manufacture for a single product, as well as the need for the product to move outside the manufacturer's network and be delivered to the patient, add to the operational complexity of drug product manufacturing. Further, technical challenges associated with maintaining the purity, activity, and efficacy of the final product during drug product processing must be overcome successfully.1

This article is the 17th in the Elements of Biopharmaceutical Production series and presents best practices to meet three of the significant technical challenges experienced in drug product manufacturing, namely, maintaining product stability during frozen storage, performing visual inspection of drug product vials, and controlling protein particulates.

BACKGROUND

Anurag S. Rathore

Protein stability can be affected by a multitude of factors that interplay during the manufacturing of biotech drug products. The need to examine product stability over a broad range of process parameters has been highlighted in the literature.1 Such an examination can be achieved by characterization studies at small scale using qualified scaled-down models or large-scale experiments designed to examine worst-case scenarios related to changes in operating conditions.2 The development of a design space in the context of developing, scaling up, and transferring freeze-dried products has been discussed in recent publications.3 It has been pointed out that when doing formulation and initial cycle development, the development scientist must be aware of the type of equipment to which the product will be transferred in the next stage of the product lifecycle.

Freezing and thawing large volumes of bulk protein solutions has become an important step in biopharmaceutical manufacturing because the flexibility it affords makes it possible to maximize productivity and align drug product logistics with market demands.4 The stability of therapeutic proteins during long-term storage has been highlighted as a key issue for product safety and efficacy.1 Storing drug substance for periods of time in the frozen state enables a decoupling of drug substance manufacturing from drug product manufacturing. A successful operation, therefore, requires an understanding of the fundamental aspects of freezing and thawing proteins as well as the impact of the practical aspects of heat and mass transfer, along with knowledge of the technology available.

Manufacturing sterile biotech products requires visual inspection of the final drug product filled in sealed containers to ensure there is no contamination from foreign particulates.5 Such inspection can be performed by humans or through an automated inspection machine (AIM). Compared to manual inspection, automated visual inspection (AVI) offers more consistency, higher speed, and improved quality of inspection. It also is cost efficient over a longer period and for higher production volumes.